Project Summary: Two main objectives of the proposed research project are to complete the first asymmetric total synthesis of the natural product pachyclavulariaenone G and investigate the therapeutic potential of this novel anticancer agent. The specific aims are as follows: 1. Develop an aldol/enyne/Diels-Alder strategy to efficiently construct the core of the target molecule. 2. Prepare significant quantities of pachyclavulariaenone G and late-stage intermediates. 3. Evaluate the potential of pachyclavulariaenone G as a medicinal agent. The total synthesis of pachyclavulariaenone G will be accomplished utilizing a synthetic route that is practical, efficient, and able to supply large quantities of the target compound as well as its synthetic intermediates: Furthermore, the strategy proposed will include the development of a novel aldol/enyne/Diels-Alder sequence to construct the seven-membered ring ether core of the molecule. This will be a useful extension of currently available methods to synthesize cyclic ethers and will be applicable to additional bioactive natural products. Once synthesized, a thorough biological evaluation will be conducted in order to investigate the antiproliferative properties of pachyclavulariaenone G. Relevance: Pachyclavulariaenone G exhibits significant anticancer properties towards leukemia and colon cancer. It is of great interest to pursue this novel medicinal agent as it will facilitate the development of improved methods to treat these life-threatening diseases. [unreadable] [unreadable] [unreadable]